Nervenheilkunde 2018; 37(11): 818-825
DOI: 10.1055/s-0038-1675711
Universitätsklinikum Ulm
Georg Thieme Verlag KG Stuttgart · New York

Antisense-Oligonukleotide II

Therapeutisches Potenzial bei neuropsychiatrischen Erkrankungen sowie ethische und gesundheitspolitische AspekteAntisense oligonucleotides IITreatment options in neuropsychiatric disorders, ethical and healthcare implications
H. Graf
1   Universitätsklinikum Ulm, Klinik für Psychiatrie und Psychotherapie III, Ulm
,
D. Lehmann
1   Universitätsklinikum Ulm, Klinik für Psychiatrie und Psychotherapie III, Ulm
2   Universität- und Rehabilitationskliniken Ulm, Neurologische Universitätsklinik, Ulm
,
A. C. Ludolph
2   Universität- und Rehabilitationskliniken Ulm, Neurologische Universitätsklinik, Ulm
,
C. D. Wurster
2   Universität- und Rehabilitationskliniken Ulm, Neurologische Universitätsklinik, Ulm
› Author Affiliations
Further Information

Korrespondenzadresse

Priv.-Doz. Dr. med. Heiko Graf
Universitätsklinikum Ulm
Klinik für Psychiatrie und Psychotherapie III
Leimgrubenweg 12–14, 89073 Ulm
Phone: 0731/50061401   
Fax: 0731/50061402   

Publication History

eingegangen am: 01 September 2018

angenommen am: 12 September 2018

Publication Date:
30 October 2018 (online)

 

Zusammenfassung

Antisense-Oligonukleotide (ASO) sind synthetische einzelsträngige Nukleinsäuren, die an die komplementäre Sequenz der prä- mRNA oder mRNA binden, Transkription und Translation beeinflussen und damit die Proteinsynthese modulieren. Im Jahr 2016 wurden 2 ASOs zur Behandlung neuromuskulärer Erkrankungen zugelassen. In tierexperimentellen sowie klinischen Studien zeigten sich vielversprechende Wirksamkeitsnachweise von ASOs zur Behandlung weiterer neurodegenerativer Erkrankungen. In diesem Artikel sollen die gegenwärtig zur Verfügung stehenden Ergebnisse zu ASOs bei der Behandlung der Alzheimer Demenz vorgestellt werden. Basierend auf in Tierexperimenten untersuchten ASOs sollen mögliche Zielstrukturen diskutiert werden, die zukünftig für einen Einsatz der ASO-Strategie in der Behandlung psychischer Erkrankungen sprechen könnten. Darüber hinaus sollen finanzielle und ethische Aspekte, die mit der Einführung von ASOs aufkamen, vorgestellt werden.


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Summary

Antisense oligonucleotides (ASO) are singlestranded nucleic acids strings that bind to a complementary sequence of the pre-mRNA or mRNA, modulate transcription and/or translation and thus, protein expression. In 2016, two ASOs were approved for treatment of neuromuscular disorders. Currently, there are further ASO drugs under research in animal models or even in clinical trials for the treatment of further neurodegenerative disorders with promising results. In this article, we present the results from studies conducted with ASO strategies for the treatment of Alzheimer`s disease. Owing to previously investigated ASOs in experimental studies, we discuss potential targets of ASO strategies and whether this approach is eligible for treatment of psychiatric disorders. Moreover, we provide an overview of the upcoming discussion regarding costs, cost-effectiveness and ethical implications of ASOs.


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Interessenkonflikt

Heiko Graf: keine Interessenkonflikte. Diana Lehmann: keine Interessenkonflikte. Claudia Diana Wurster: Beratertätigkeit für die Firma Hoffmann-La Roche; Honorarvorträge für die Firma Biogen sowie Teilnahme an einem AdBoard Meeting der Firma Biogen. Albert Ludolph: Unterstützung für klinische Forschungsprojekte durch AB Science, Biogen Idec, Cytokinetics, GSK, Orion Pharam, Novartis, TauRx Therapeutics Ltd. und TEVA Pharmaceuticals. Honorare als Berater von Mitsubishi, Orion Pharma, Novartis, Teva sowie für lectures fees von Biogen und Ionis sowie als AdBoard-Mitglied von Biogen, Treeway, Hoffmann-La Roche und Novartis.

  • Literatur

  • 1 Evers MM, Toonen LJA, van Roon-Mom WMC. Antisense oligonucleotides in therapy for neurodegenerative disorders. Adv Drug Deliv Rev 2015; 87: 90-103.
  • 2 Bennett CF, Baker BF, Pham N, Swayze E, Geary RS. Pharmacology of Antisense Drugs. Annu Rev Pharmacol Toxicol 2017; 57: 81-105.
  • 3 Kendler KS, Zerbin-Rüdin E. Abstract and Review of “Studien Über Vererbung und Entstehung Geistiger Störungen. I. Zur Vererbung und Neuentstehung der Dementia praecox.” (Studies on the Inheritance and Origin of Mental Illness: I. To the Problem of the Inheritance and Primary Origin of Dementia Praecox.). Am J Med Genet – Semin Med Genet 1996; 67: 338-342.
  • 4 Luxenburger H. Vorläufiger Bericht über psychiatrische Serienuntersuchungen an Zwillingen. Zeitschrift für die gesamte Neurol und Psychiatr 1928; 116: 297-326.
  • 5 Heston LL. Psychiatric disorders in foster home reared children of schizophrenic mothers. Br J Psychiatry 1966; 112: 819-825.
  • 6 Smoller JW, Andreassen OA, Edenberg HJ, Faraone S V, Glatt SJ, Kendler KS. Psychiatric genetics and the structure of psychopathology. Mol Psychiatry 2018; 4634: 1-13.
  • 7 Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia: A systematic review and metaanalysis. Alzheimer’s Dement 2013; 09: 63-75.
  • 8 Scheltens P, Blennow K, Breteler MMB, de Strooper B, Frisoni GB, Salloway S, Van der Flier WM. Alzheimer’s disease. Lancet 2016; 388: 505-517.
  • 9 Braak H, Tredici KD. Neuroanatomy and Pathology of Sporadic Alzheimer’s Disease. New York: Springer; 2015
  • 10 O’Brien RJ, Wong PC. Amyloid Precursor Protein Processing and Alzheimer’s Disease. Annu Rev Neurosci 2011; 34: 185-204.
  • 11 Schoch KM, Miller TM. Antisense Oligonucleotides: Translation from Mouse Models to Human Neurodegenerative Diseases. Neuron 2017; 94: 1056-1070.
  • 12 St George-Hyslop PH. Molecular genetics of Alzheimer’s disease. Biol Psychiatry 2000; 47: 183-199.
  • 13 Kumar VB, Farr SA, Flood JF, Kamlesh V, Franko M, Banks WA, Morley JE. Site-directed antisense oligonucleotide decreases the expression of amyloid precursor protein and reverses deficits in learning and memory in aged SAMP8 mice. Peptides 2000; 21: 1769-1775.
  • 14 Farr SA, Erickson MA, Niehoff ML, Banks WA, Morley JE. Central and peripheral administration of antisense oligonucleotide targeting amyloid-β protein precursor improves learning and memory and reduces neuroinflammatory cytokines in Tg2576 (AβPPswe) mice. J Alzheimer’s Dis 2014; 40: 1005-1016.
  • 15 Yamazaki Y, Painter MM, Bu G, Kanekiyo T. Apolipoprotein E as a Therapeutic Target in Alzheimer’s Disease: A Review of Basic Research and Clinical Evidence. CNS Drugs 2016; 30: 773-789.
  • 16 Corder E, Saunders A, Strittmatter W, Schmechel D, Gaskell P, Small G, Roses A, Haines J, Pericak-Vance M. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 1993; 261: 921-923.
  • 17 Hinrich AJ, Jodelka FM, Chang JL, Brutman D, Bruno AM, Briggs CA, James BD, Stutzmann GE, Bennett DA, Miller SA, Rigo F, Marr RA, Hastings ML. Therapeutic correction of ApoER2 splicing in Alzheimer’s disease mice using antisense oligonucleotides. EMBO Mol Med 2016; 08: 328-345.
  • 18 Morris M, Maeda S, Vossel K, Mucke L. The Many Faces of Tau. Neuron 2011; 70: 410-426.
  • 19 Kolarova M, García-Sierra F, Bartos A, Ricny J, Ripova D. Structure and pathology of tau protein in Alzheimer disease. Int J Alzheimers Dis 2012; 201: 731526.
  • 20 Liu F, Gong C-X. Tau exon 10 alternative splicing and tauopathies. Mol Neurodegener 2008; 03: 8.
  • 21 DeVos SL, Miller RL, Schoch KM, Holmes BB, Kebodeaux CS, Wegener AJ, Chen G, Shen T, Tran H, Nichols B, Zanardi TA, Kordasiewicz HB, Swayze EE, Bennett CF, Diamond MI, Miller TM. Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy. Sci Transl Med 2017; 09: 1-14.
  • 22 Schoch KMM, DeVos SLL, Miller RLL, Chun SJJ, Norrbom M, Wozniak DFF, Dawson HNN, Bennett CF, Rigo F, Miller TMM. Increased 4R-Tau Induces Pathological Changes in a Human-Tau Mouse Model. Neuron 2016; 90: 941-947.
  • 23 Zamecnik PC, Stephenson ML. Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide. Proc Natl Acad Sci USA 1978; 75: 280-284.
  • 24 Stephenson ML, Zamecnik PC. Inhibition of Rous sarcoma viral RNA translation by a specific oligodeoxyribonucleotide. Proc Natl Acad Sci 1978; 75: 285-288.
  • 25 Herzog H. Regional distribution of Y-receptor subtype mRNAs in rat brain. Eur J Neurosci 1999; 11: 1431-1448.
  • 26 Kornhuber J, Zoicas I. Neuropeptide Y prolongs non-social memory and differentially affects acquisition, consolidation, and retrieval of non-social and social memory in male mice. Sci Rep 2017; 07: 6821.
  • 27 Blomqvist AG, Herzog H. Y-receptor subtypes – how many more?. Trends Neurosci 1997; 20: 294-298.
  • 28 Stanley BG, Leibowitz SF. Neuroreptide Y: Stimulation of feeding and drinking by injection into the paraventricular nucleus. Life Sci 1984; 35: 2635-2642.
  • 29 Colmers WF, Bleakman D. Effects of neuropeptide Y on the electrical properties of neurons. Trends Neurosci 1994; 17: 373-379.
  • 30 Vezzani A, Sperk G, Colmers WF. Neuropeptide Y: emerging evidence for a functional role in seizure modulation. Trends Neurosci 1999; 22: 25-30.
  • 31 Michalkiewicz M, Michalkiewicz T, Kreulen DL, McDougall SJ. Increased blood pressure responses in neuropeptide Y transgenic rats. Am J Physiol Regul Integr Comp Physiol 2001; 281: 417-426.
  • 32 Magni P. Hormonal control of the neuropeptide Y system. Curr Protein Pept Sci 2003; 04: 45-57.
  • 33 Hökfelt T, Stanic D, Sanford SD, Gatlin JC, Nilsson I, Paratcha G, Ledda F, Fetissov S, Lindfors C, Herzog H, Johansen JE, Ubink R, Pfenninger KH. NPY and its involvement in axon guidance, neurogenesis, and feeding. Nutrition 2008; 24: 860-868.
  • 34 Sajdyk TJ, Vandergriff MG, Gehlert DR. Amygdalar neuropeptide Y Y1 receptors mediate the anxiolytic-like actions of neuropeptide Y in the social interaction test. Eur J Pharmacol 1999; 368: 143-147.
  • 35 Sajdyk TJ, Schober DA, Smiley DL, Gehlert DR. Neuropeptide Y-Y2 receptors mediate anxiety in the amygdala. Pharmacol Biochem Behav 2002; 71: 419-423.
  • 36 Redrobe JP, Dumont Y, Fournier A, Quirion R. The neuropeptide Y (NPY) Y1 receptor subtype mediates NPY-induced antidepressant-like activity in the mouse forced swimming test. Neuropsychopharmacology 2002; 26: 615-624.
  • 37 Enman NM, Sabban EL, McGonigle P, Van Bockstaele EJ. Targeting the neuropeptide Y system in stress-related psychiatric disorders. Neurobiol Stress 2015; 01: 33-43.
  • 38 Wahlestedt C, Pich EM, Koob GF, Yee F, Heilig M. Modulation of anxiety and neuropeptide Y-Y1 receptors by antisense oligodeoxynucleotides. Science 1993; 259: 528-531.
  • 39 Akabayashi A, Wahlestedt C, Alexander JT, Leibowitz SF. Specific inhibition of endogenous neuropeptide Y synthesis in arcuate nucleus by antisense oligonucleotides suppresses feeding behavior and insulin secretion. Mol Brain Res 1994; 21: 55-61.
  • 40 Castren E, Voikar V, Rantamaki T. Role of neurotrophic factors in depression. Curr Opin Pharmacol 2007; 07: 18-21.
  • 41 Castren E, Antila H. Neuronal plasticity and neurotrophic factors in drug responses. Mol Psychiatry 2017; 22: 1085-1095.
  • 42 Modarresi F, Faghihi MA, Lopez-Toledano MA, Fatemi RP, Magistri M, Brothers SP, Van Der Brug MP, Wahlestedt C. Inhibition of natural antisense transcripts in vivo results in gene-specific transcriptional upregulation. Nat Biotechnol 2012; 30: 453-459.
  • 43 Zhang M, Creese I. Antisense oligodeoxynucleotide reduces brain dopamine D2 receptors: behavioral correlates. Neurosci Lett 1993; 161: 223-226.
  • 44 Andoh H, Yoshikawa M, Kawaguchi M, Matsumoto H, Yamazaki K, Oka T. The selective action of D2 dopamine receptor antisense oligodeoxynucleotide on the expression of the dopamine receptor subtype mRNA in rat striatum. Tokai J Exp Clin Med 2006; 31: 73-77.
  • 45 Silvestri S, Seeman M V, Negrete JC, Houle S, Shammi CM, Remington GJ, Kapur S, Zipursky RB, Wilson AA, Christensen BK, Seeman P. Increased dopamine D2receptor binding after long-term treatment with antipsychotics in humans: A clinical PET study. Psychopharmacology 2000; 152: 174-180.
  • 46 McCammon JM, Sive H. Challenges in understanding psychiatric disorders and developing therapeutics: a role for zebrafish. Dis Model Mech 2015; 08: 647-656.
  • 47 Schoch KM, Miller TM. Antisense Oligonucleotides: Translation from Mouse Models to Human Neurodegenerative Diseases. Neuron 2017; 94: 1056-1070.
  • 48 Khorkova O, Wahlestedt C. Oligonucleotide therapies for disorders of the nervous system. Nat Biotechnol 2017; 35: 249-263.
  • 49 Cunha C, Angelucci A, D’Antoni A, Dobrossy MD, Dunnett SB, Berardi N, Brambilla R. Brain-derived neurotrophic factor (BDNF) overexpression in the forebrain results in learning and memory impairments. Neurobiol Dis 2009; 33: 358-368.
  • 50 Dalakas MC. Gene therapy for Duchenne muscular dystrophy: Balancing good science, marginal efficacy, high emotions and excessive cost. Ther Adv Neurol Disord 2017; 10: 293-296.
  • 51 Gellad WF, Kesselheim AS. Accelerated Approval and Expensive Drugs – A Challenging Combination. N Engl J Med 2017; 376: 2001-2004.
  • 52 The Lancet Neurology. Treating rare disorders: time to act on unfair prices. Lancet Neurol 2017; 16: 761.
  • 53 Prasad V. Nusinersen for spinal muscular atrophy are we paying too much for too little?. JAMA Pediatr 2018; 172: 123-125.

Korrespondenzadresse

Priv.-Doz. Dr. med. Heiko Graf
Universitätsklinikum Ulm
Klinik für Psychiatrie und Psychotherapie III
Leimgrubenweg 12–14, 89073 Ulm
Phone: 0731/50061401   
Fax: 0731/50061402   

  • Literatur

  • 1 Evers MM, Toonen LJA, van Roon-Mom WMC. Antisense oligonucleotides in therapy for neurodegenerative disorders. Adv Drug Deliv Rev 2015; 87: 90-103.
  • 2 Bennett CF, Baker BF, Pham N, Swayze E, Geary RS. Pharmacology of Antisense Drugs. Annu Rev Pharmacol Toxicol 2017; 57: 81-105.
  • 3 Kendler KS, Zerbin-Rüdin E. Abstract and Review of “Studien Über Vererbung und Entstehung Geistiger Störungen. I. Zur Vererbung und Neuentstehung der Dementia praecox.” (Studies on the Inheritance and Origin of Mental Illness: I. To the Problem of the Inheritance and Primary Origin of Dementia Praecox.). Am J Med Genet – Semin Med Genet 1996; 67: 338-342.
  • 4 Luxenburger H. Vorläufiger Bericht über psychiatrische Serienuntersuchungen an Zwillingen. Zeitschrift für die gesamte Neurol und Psychiatr 1928; 116: 297-326.
  • 5 Heston LL. Psychiatric disorders in foster home reared children of schizophrenic mothers. Br J Psychiatry 1966; 112: 819-825.
  • 6 Smoller JW, Andreassen OA, Edenberg HJ, Faraone S V, Glatt SJ, Kendler KS. Psychiatric genetics and the structure of psychopathology. Mol Psychiatry 2018; 4634: 1-13.
  • 7 Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia: A systematic review and metaanalysis. Alzheimer’s Dement 2013; 09: 63-75.
  • 8 Scheltens P, Blennow K, Breteler MMB, de Strooper B, Frisoni GB, Salloway S, Van der Flier WM. Alzheimer’s disease. Lancet 2016; 388: 505-517.
  • 9 Braak H, Tredici KD. Neuroanatomy and Pathology of Sporadic Alzheimer’s Disease. New York: Springer; 2015
  • 10 O’Brien RJ, Wong PC. Amyloid Precursor Protein Processing and Alzheimer’s Disease. Annu Rev Neurosci 2011; 34: 185-204.
  • 11 Schoch KM, Miller TM. Antisense Oligonucleotides: Translation from Mouse Models to Human Neurodegenerative Diseases. Neuron 2017; 94: 1056-1070.
  • 12 St George-Hyslop PH. Molecular genetics of Alzheimer’s disease. Biol Psychiatry 2000; 47: 183-199.
  • 13 Kumar VB, Farr SA, Flood JF, Kamlesh V, Franko M, Banks WA, Morley JE. Site-directed antisense oligonucleotide decreases the expression of amyloid precursor protein and reverses deficits in learning and memory in aged SAMP8 mice. Peptides 2000; 21: 1769-1775.
  • 14 Farr SA, Erickson MA, Niehoff ML, Banks WA, Morley JE. Central and peripheral administration of antisense oligonucleotide targeting amyloid-β protein precursor improves learning and memory and reduces neuroinflammatory cytokines in Tg2576 (AβPPswe) mice. J Alzheimer’s Dis 2014; 40: 1005-1016.
  • 15 Yamazaki Y, Painter MM, Bu G, Kanekiyo T. Apolipoprotein E as a Therapeutic Target in Alzheimer’s Disease: A Review of Basic Research and Clinical Evidence. CNS Drugs 2016; 30: 773-789.
  • 16 Corder E, Saunders A, Strittmatter W, Schmechel D, Gaskell P, Small G, Roses A, Haines J, Pericak-Vance M. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 1993; 261: 921-923.
  • 17 Hinrich AJ, Jodelka FM, Chang JL, Brutman D, Bruno AM, Briggs CA, James BD, Stutzmann GE, Bennett DA, Miller SA, Rigo F, Marr RA, Hastings ML. Therapeutic correction of ApoER2 splicing in Alzheimer’s disease mice using antisense oligonucleotides. EMBO Mol Med 2016; 08: 328-345.
  • 18 Morris M, Maeda S, Vossel K, Mucke L. The Many Faces of Tau. Neuron 2011; 70: 410-426.
  • 19 Kolarova M, García-Sierra F, Bartos A, Ricny J, Ripova D. Structure and pathology of tau protein in Alzheimer disease. Int J Alzheimers Dis 2012; 201: 731526.
  • 20 Liu F, Gong C-X. Tau exon 10 alternative splicing and tauopathies. Mol Neurodegener 2008; 03: 8.
  • 21 DeVos SL, Miller RL, Schoch KM, Holmes BB, Kebodeaux CS, Wegener AJ, Chen G, Shen T, Tran H, Nichols B, Zanardi TA, Kordasiewicz HB, Swayze EE, Bennett CF, Diamond MI, Miller TM. Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy. Sci Transl Med 2017; 09: 1-14.
  • 22 Schoch KMM, DeVos SLL, Miller RLL, Chun SJJ, Norrbom M, Wozniak DFF, Dawson HNN, Bennett CF, Rigo F, Miller TMM. Increased 4R-Tau Induces Pathological Changes in a Human-Tau Mouse Model. Neuron 2016; 90: 941-947.
  • 23 Zamecnik PC, Stephenson ML. Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide. Proc Natl Acad Sci USA 1978; 75: 280-284.
  • 24 Stephenson ML, Zamecnik PC. Inhibition of Rous sarcoma viral RNA translation by a specific oligodeoxyribonucleotide. Proc Natl Acad Sci 1978; 75: 285-288.
  • 25 Herzog H. Regional distribution of Y-receptor subtype mRNAs in rat brain. Eur J Neurosci 1999; 11: 1431-1448.
  • 26 Kornhuber J, Zoicas I. Neuropeptide Y prolongs non-social memory and differentially affects acquisition, consolidation, and retrieval of non-social and social memory in male mice. Sci Rep 2017; 07: 6821.
  • 27 Blomqvist AG, Herzog H. Y-receptor subtypes – how many more?. Trends Neurosci 1997; 20: 294-298.
  • 28 Stanley BG, Leibowitz SF. Neuroreptide Y: Stimulation of feeding and drinking by injection into the paraventricular nucleus. Life Sci 1984; 35: 2635-2642.
  • 29 Colmers WF, Bleakman D. Effects of neuropeptide Y on the electrical properties of neurons. Trends Neurosci 1994; 17: 373-379.
  • 30 Vezzani A, Sperk G, Colmers WF. Neuropeptide Y: emerging evidence for a functional role in seizure modulation. Trends Neurosci 1999; 22: 25-30.
  • 31 Michalkiewicz M, Michalkiewicz T, Kreulen DL, McDougall SJ. Increased blood pressure responses in neuropeptide Y transgenic rats. Am J Physiol Regul Integr Comp Physiol 2001; 281: 417-426.
  • 32 Magni P. Hormonal control of the neuropeptide Y system. Curr Protein Pept Sci 2003; 04: 45-57.
  • 33 Hökfelt T, Stanic D, Sanford SD, Gatlin JC, Nilsson I, Paratcha G, Ledda F, Fetissov S, Lindfors C, Herzog H, Johansen JE, Ubink R, Pfenninger KH. NPY and its involvement in axon guidance, neurogenesis, and feeding. Nutrition 2008; 24: 860-868.
  • 34 Sajdyk TJ, Vandergriff MG, Gehlert DR. Amygdalar neuropeptide Y Y1 receptors mediate the anxiolytic-like actions of neuropeptide Y in the social interaction test. Eur J Pharmacol 1999; 368: 143-147.
  • 35 Sajdyk TJ, Schober DA, Smiley DL, Gehlert DR. Neuropeptide Y-Y2 receptors mediate anxiety in the amygdala. Pharmacol Biochem Behav 2002; 71: 419-423.
  • 36 Redrobe JP, Dumont Y, Fournier A, Quirion R. The neuropeptide Y (NPY) Y1 receptor subtype mediates NPY-induced antidepressant-like activity in the mouse forced swimming test. Neuropsychopharmacology 2002; 26: 615-624.
  • 37 Enman NM, Sabban EL, McGonigle P, Van Bockstaele EJ. Targeting the neuropeptide Y system in stress-related psychiatric disorders. Neurobiol Stress 2015; 01: 33-43.
  • 38 Wahlestedt C, Pich EM, Koob GF, Yee F, Heilig M. Modulation of anxiety and neuropeptide Y-Y1 receptors by antisense oligodeoxynucleotides. Science 1993; 259: 528-531.
  • 39 Akabayashi A, Wahlestedt C, Alexander JT, Leibowitz SF. Specific inhibition of endogenous neuropeptide Y synthesis in arcuate nucleus by antisense oligonucleotides suppresses feeding behavior and insulin secretion. Mol Brain Res 1994; 21: 55-61.
  • 40 Castren E, Voikar V, Rantamaki T. Role of neurotrophic factors in depression. Curr Opin Pharmacol 2007; 07: 18-21.
  • 41 Castren E, Antila H. Neuronal plasticity and neurotrophic factors in drug responses. Mol Psychiatry 2017; 22: 1085-1095.
  • 42 Modarresi F, Faghihi MA, Lopez-Toledano MA, Fatemi RP, Magistri M, Brothers SP, Van Der Brug MP, Wahlestedt C. Inhibition of natural antisense transcripts in vivo results in gene-specific transcriptional upregulation. Nat Biotechnol 2012; 30: 453-459.
  • 43 Zhang M, Creese I. Antisense oligodeoxynucleotide reduces brain dopamine D2 receptors: behavioral correlates. Neurosci Lett 1993; 161: 223-226.
  • 44 Andoh H, Yoshikawa M, Kawaguchi M, Matsumoto H, Yamazaki K, Oka T. The selective action of D2 dopamine receptor antisense oligodeoxynucleotide on the expression of the dopamine receptor subtype mRNA in rat striatum. Tokai J Exp Clin Med 2006; 31: 73-77.
  • 45 Silvestri S, Seeman M V, Negrete JC, Houle S, Shammi CM, Remington GJ, Kapur S, Zipursky RB, Wilson AA, Christensen BK, Seeman P. Increased dopamine D2receptor binding after long-term treatment with antipsychotics in humans: A clinical PET study. Psychopharmacology 2000; 152: 174-180.
  • 46 McCammon JM, Sive H. Challenges in understanding psychiatric disorders and developing therapeutics: a role for zebrafish. Dis Model Mech 2015; 08: 647-656.
  • 47 Schoch KM, Miller TM. Antisense Oligonucleotides: Translation from Mouse Models to Human Neurodegenerative Diseases. Neuron 2017; 94: 1056-1070.
  • 48 Khorkova O, Wahlestedt C. Oligonucleotide therapies for disorders of the nervous system. Nat Biotechnol 2017; 35: 249-263.
  • 49 Cunha C, Angelucci A, D’Antoni A, Dobrossy MD, Dunnett SB, Berardi N, Brambilla R. Brain-derived neurotrophic factor (BDNF) overexpression in the forebrain results in learning and memory impairments. Neurobiol Dis 2009; 33: 358-368.
  • 50 Dalakas MC. Gene therapy for Duchenne muscular dystrophy: Balancing good science, marginal efficacy, high emotions and excessive cost. Ther Adv Neurol Disord 2017; 10: 293-296.
  • 51 Gellad WF, Kesselheim AS. Accelerated Approval and Expensive Drugs – A Challenging Combination. N Engl J Med 2017; 376: 2001-2004.
  • 52 The Lancet Neurology. Treating rare disorders: time to act on unfair prices. Lancet Neurol 2017; 16: 761.
  • 53 Prasad V. Nusinersen for spinal muscular atrophy are we paying too much for too little?. JAMA Pediatr 2018; 172: 123-125.